Gurley Bill J, Gardner Stephanie F, Hubbard Martha A, Williams D Keith, Gentry W Brooks, Cui Yanyan, Ang Catharina Y W
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Drugs Aging. 2005;22(6):525-39. doi: 10.2165/00002512-200522060-00006.
Elderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.
Twelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported 'active' phytochemicals was determined for each supplement.
Comparisons of pre- and post-St John's wort phenotypic ratios revealed significant induction of CYP3A4 (approximately 140%) and CYP2E1 activity (approximately 28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.
Elderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John's wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.
老年患者更有可能同时服用处方药和植物补充剂，因此可能易发生草药-药物相互作用。植物化学物质介导的细胞色素P450（CYP）活性调节可能是许多草药-药物相互作用的基础。一些证据表明，老年人的CYP活性可能会降低。如果是这样，草药介导的CYP活性变化在该人群中可能具有更大的临床相关性。在本研究中，使用单次时间点的表型代谢率来确定长期补充圣约翰草、大蒜油、人参和银杏叶是否会影响老年受试者的CYP1A2、CYP2D6、CYP2E1或CYP3A4活性。
12名年龄在60至76岁之间（平均年龄67岁）的健康志愿者被随机分配接受每种植物补充剂28天，随后有30天的洗脱期。在补充前和补充结束时给予咪达唑仑、咖啡因、氯唑沙宗和异喹胍的探针药物鸡尾酒。使用1-羟基咪达唑仑/咪达唑仑血清比率（1小时）、对黄嘌呤/咖啡因血清比率（6小时）、6-羟基氯唑沙宗/氯唑沙宗血清比率（2小时）和异喹胍尿回收率（8小时）分别测定补充前和补充后CYP3A4、CYP1A2、CYP2E1和CYP2D6的表型比率。测定每种补充剂中所谓“活性”植物化学物质的含量。
圣约翰草补充前后表型比率的比较显示，CYP3A4活性（约140%）和CYP2E1活性（约28%）有显著诱导。大蒜油使CYP2E1活性降低约22%。人参对CYP2D6的抑制具有统计学意义，但作用幅度（约7%）似乎不具有临床相关性。本研究中测试的任何补充剂似乎都不影响CYP1A2活性。
老年受试者与年轻受试者一样，易受草药介导的CYP活性变化影响，尤其是涉及圣约翰草的变化。由CYP活性改变引起的药代动力学草药-药物相互作用可能会对药物疗效和/或毒性产生不利影响。与早期使用年轻受试者的研究相比，数据表明CYP对植物补充剂的反应性可能存在一些与年龄相关的变化。因此，应强烈劝阻老年人同时服用植物补充剂和处方药。
